Medical implants, such as dental implants, orthopaedic implants, prosthesis and vascular stents are commonly made of titanium and/or a titanium alloy. Titanium is the material most frequently used as implant in bone, as it has outstanding physical and biological properties, such as low density, mechanical strength, and chemical resistance against body fluids. Titanium is a well-known biocompatible material, successfully used for the manufacturing of prostheses and dental implants. Its surface chemistry and structure are prime factors governing bone integration.
Dental implants are utilized in dental restoration procedures in patients having lost one or more of their teeth. A dental implant comprises a dental fixture, which is utilized as an artificial tooth root replacement. Thus, the dental fixture serves as a root for a new tooth. Typically, the dental fixture is a titanium screw which has a roughened surface in order to expand the area of tissue contact. The titanium screw is surgically implanted into the jawbone, where after the bone tissue grows around the screw. This process is called osseointegration, because osteoblasts grow on and into the rough surface of the implanted screw. By means of osseointegration, a rigid installation of the screw is obtained.
Once the titanium screw is firmly anchored in the jawbone, it may be prolonged by attachment of an abutment to the screw. The abutment may, just as the screw, be made of titanium or a titanium alloy. The shape and size of the utilized abutment are adjusted such that it precisely reaches up through the gingiva after attachment to the screw. A dental restoration such as a crown, bridge or denture may then be attached to the abutment. Alternatively, the titanium screw has such a shape and size that it reaches up through the gingiva after implantation, whereby no abutment is needed and a dental restoration such as a crown, bridge or denture may be attached directly to the screw.
Orthopedic implants are utilized for the preservation and restoration of the function in the musculoskeletal system, particularly joints and bones, including alleviation of pain in these structures. Vascular stents are tubular implants arranged for insertion into blood vessels in order to prevent or counteract a localized flow constriction, i.e. they counteract significant decreases in blood vessel diameter.
As already mentioned above, titanium (Ti) is commonly used in dental and orthopaedic applications and in vascular stents. The stable oxides that form readily on Ti surfaces have been reported to attribute to its excellent biocompatibility. However, it has also been reported that bone response to implant surfaces was dependent on the chemical and physical properties of Ti surfaces, thereby affecting implant success. As such, attention has been focused on the surface preparation of Ti implants.
As the surface of titanium and its alloys are bioinert, a fibrous tissue of variable thickness may form, encapsulating and isolating the implants from the surrounding environment when they are used for osseointegration. This lack of osseointegration is being addressed through the modification of the implant surface by bonding bioactive coatings. Current research on modification of implant surfaces focuses on making virtual bioinert materials become bioactive, or rather to influence the types of proteins absorbed at the surface readily after implantation. The assortment of surface modifications ranges from non-biological coatings, such as carbide, fluorine, calcium, hydroxyl apatite or calcium phosphate, to coatings that are to mimic the biological surroundings using lipid mono- or bi-layers, growth factors, proteins, and/or peptides.
The biocompatibility of prostheses or implants has been proposed to improve by binding or integrating various active biomolecules to the surface of the prosthesis, e.g. on to the metallic surface of a titanium prosthesis. It has been the aim with implants prepared this way that they have improved fit; exhibit increased tissue stickiness and increased tissue compatibility; have a biologically active surface for increased cell growth, differentiation and maturation; exhibit reduced immunoreactivity; exhibit antimicrobial activity; exhibit increased biomineralisation capabilities; result in improved wound and/or bone healing; lead to improved bone density; have reduced “time to load” and cause less inflammation.
Various surface mechanical, chemical, and physical surface modification methods have been applied to titanium alloys including machining or polishing, acidic or alkaline treatment, anodic oxidation, chemical vapor deposition, biochemical modification through silanization, physical vapor deposition, ion implantation, and glow discharge plasma treatment. For biological applications, plasma treatment using radio frequency glow discharge (RFGD) is especially attractive as it may be used to deposit active functional groups for covalent attachment of other polymers or biomolecules. Similarly, silane coupling agents with a terminal functional group have been used for surface modification of inorganic silicas as well as metallic materials. Others have reported the modification of titanium surfaces by alkylsilanes to form organic films with good stability, furthermore, coupling agents such as organofunctional trialkoxysilanes have been applied to form durable chemical bonding between inorganic and organic molecules (or moieties) (Liu. Chu et al. 2004 ).
However, inositol phosphates (IPs) have never been reported to be covalently attached to the metal surface, directly or through a linker.
Myo-inositol-1,2,3,4,5,6-hexakisphosphate (IP6 ), also known as phytic acid or phytate (when in a salt form) is a molecule abundant in vegetable seeds and legumes. It is also naturally present in all mammalian biological fluids (e.g. urine and plasma) due to exogenous administration, mainly dietary ingestion. Several potential beneficial effects of this compound on human health have recently been demonstrated. In particular, IP6 functions as an inhibitor of bone resorption in animal models of osteoporosis. It is adsorbed on the surface of hydroxyapatite (HAP), the mineral constituent of bone, decreasing the progressive loss of bone mass acting as a potent inhibitor of hydroxyapatite dissolution.
The structure of IPs and their affinity for calcium ions give them properties as crystallization inhibitors, as well as antiresorptive properties (Grases. Sanchis et al. 2010).
Phytate has previously been described in the context of biocompatible medical implants, such as e.g. in WO2004/024202, which disclose biocompatible implants having a coating of a phosphoric containing metal oxide which is formed by an anodic treatment. The coating is added to the implant to facilitate its attachment to bone tissue.
Furthermore, in U.S. Pat. No. 5,478,237, similar to WO 2004/024202, implants are also produced by anodic treatment. The coatings on the implants presented additionally comprise Ca and P ions for improving bone growth to the implant described therein.
However, anodic treatment does not produce covalent binding of the biomolecules, but involves the formation of an adsorbed film layer containing oxygen and the biomolecules (with Ca and P, for example) on the metal surface.
Despite the availability of biocompatible implants in the art today, there is still a need to to identify alternative biocompatible implants which further may facilitate osseointegration of an implant when introduced into a mammalian body. Accordingly, an object of the present invention is to overcome some of the problems associated with the implants of the prior art, which are mainly related to the difficulties of permanently binding bioactive molecules to an implant surface. Furthermore, there is a limitation of most of the available techniques with regards to the physical absorption (labile union) of these compounds onto the surface of the implant.